1. Field of the Invention
The present invention relates to long chain carboxylic acid imide esters or their salts. The long chain carboxylic acid imide esters or their salts are useful for modifying enzymes or proteins (hereinafter enzymes and proteins are referred to simply as "proteins") having biological activities, to give their derivatives which have, while retaining most of the original biological activities, an extremely prolonged plasma half-life as compared with the proteins and no antigenecities and can be administered to animals.
2. Description of the Prior Art
A number of attempts have been made to improve proteins with various modifiers. Polyethylene glycol (hereinafter referred to as "PEG") is one of those modifiers which have been studied most actively in recent years. PEG is being used for modifying, for example, anticancer agents such as asparaginase, arginase and interleukin-2 (hereinafter referred to as "IL-2"), thrombolytic agents such as urokinase, streptokinase, tissue plasminogen activator (hereinafter referred to as "TPA"), treating agents for enzyme deficiency diseases, such as .beta.-glucosidase, .beta.-glucuronidase, .alpha.-galactosidase and adenosine deaminase, gout treating agents such as uricase, anti-inflammatory agents or anti-ischemic agents such as superoxide dismutase (hereinafter sometimes referred to as "SOD"), diabetes treating agent of insulin, and hyperbilirubinemia treating agent of bilirubin oxidase. In more recent years, an attempt was made to modify granulocyte colony-stimulating factor (hereinafter referred to as "G-CSF"), which is one of hematopoietic factors, with PEG to prolong its plasma half-life and to use it for treating hematopoietic disorder and like purposes [Japanese Patent Application Laid-open No. 316400/1989 and International Laid-open No. WO90/06952]. There have been studied and used modifiers other than PEG, and there examples are natural polymers, such as serum albumin and dextran, and polyaspartic acid, partially half-esterified styrene-maleic anhydride copolymer (hereinafter referred to as "SMA") and reactable derivatives of long chain fatty acids ["Tanpakushitsu Haiburido" ("Protein Hybrids"), Chapters 1, 2, 3 and 6, published by Kyoritsu Shuppan Co. on Apr. 1, 1987, "Zoku Tanpakushitsu Haiburido" ("Protein Hybrids; a 2nd series"), Chapters 3, 4 and 6, published by Kyoritsu Shuppan Co. on May 20, 1988 and "SOD No Shinchiken" ("New Findings on SOD" ), p. 107, published by Nihon Akuseru Shupuringa Co. on Dec. 20, 1990].
SOD modified with serum albumin has antigenicity [Agents and Actions, 10, 231 (1980)]. Although the structures of other modifiers including dextran, PEG, polyaspartic acid and SMA can be specified from the viewpoint of polymer chemistry, they have a certain distribution in their molecular weights. The molecular weights of proteins modified with these polymers are therefore not constant, which is a problem in practical applications in view of the current situation in which the compound to be used as a medicinally active ingredient should preferably have a single chemical structure.
Accordingly, an object of the present invention is to provide a novel long chain carboxylic acid imide ester or its salts that can modify proteins to obtain protein derivatives having significantly prolonged plasma half-life as compared with that of unmodified proteins and no antigenicity and can be administered to animals.
This object was well as other objects and advantages of the present invention will be apparent to those skilled in the art from the following detailed description.